Nonalcoholic fatty liver disease (NAFLD) is a major public health issue affecting ~30% of Americans. If left untreated, NAFLD can progress to nonalcoholic steatohepatitis (NASH), and then to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD remains poorly understood. Identifying novel pathways that can be targeted to improve NAFLD, and consequently NASH, is thus an imperative need. Given that NAFLD is a disorder of abnormal liver lipid accumulation, it is logical that the pathogenesis involves nutrient sensing pathways that regulate hepatic lipid homeostasis. To better probe these pathways in NAFLD, I set out to study the protein folliculin (FLCN), which has recently been linked to nutrient sensing in adipose and other metabolic tissues. Mechanistically, FLCN activates RagC, which then recruits mTORC1 to promote cytoplasmic sequestration of the transcription factor E3 (TFE3), a key driver of lysosomal biogenic genes. FLCN is expressed abundantly in the liver, but nothing is known of its role in this highly metabolic tissue. My data show that liver-specific Flcn deletion powerfully protects against NAFLD in a TFE3-dependent manner. Further preliminary data reveal Flcn liver deletion causes suppressed de novo lipogenesis (DNL) genes, induced fatty acid oxidation (FAO) genes, increased liver triglyceride secretion, and increased hepatic lipophagy. Thus, I hypothesize (aim 1) that, physiologically, Flcn deletion coordinates through these 4 pathways a coordinated program to prevent steatosis, and that these effects are TFE3-dependent; I will study these pathways through state-of-the-art functional assays. I also hypothesize, (aim 2) mechanistically, that Flcn-null livers are protected from NAFLD due to the inhibition of FLCN-driven RagC activation. This then allows TFE3 to translocate into the nucleus and regulate a gene expression program to protect from steatosis, specifically (1) competing with SREBP-1c to suppress DNL genes, and (2) inducing PGC-1alpha to activate FAO genes, as suggested by my TFE3 ChIP-seq data. I will study these mechanisms through ChIP, luciferase assays, and genetic mouse models. Finally, I hypothesize that (aim 3) Flcn liver deletion will also protect against NASH, which I will test using a NASH-inducing diet and genetic mouse models. My work will illuminate the role of FLCN in NAFLD and NASH, and if successful, will provide a promising target for future therapies. These studies serve as the basis for my pre-doctoral fellowship application to the National Institute of Diabetes and Digestive and Kidney Diseases awarded to M.D./Ph.D. applicants. My training plan is geared toward becoming a physician-scientist: through the pursuit of this highly clinically relevant research topic and through continued exposure to clinical medicine and translational research, I will develop the skills necessary to blend clinical practice and basic science in my career. Moreover, training under the excellent mentorship of a physician-scientist (Dr. Zoltan Arany) and being a part of the well-established M.D./Ph.D. program at the University of Pennsylvania, I am in an ideal environment to pursue my dream career.
Nonalcoholic fatty liver disease (NAFLD) affects ~30% of individuals in the U.S., and if left untreated, it can progress to nonalcoholic steatohepatitis (NASH) and consequently to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD remains poorly understood, and thus identifying novel pathways that can be targeted to improve this spectrum of diseases is an imperative clinical need. My studies will shed light on the role of a novel protein folliculin in NAFLD and NASH, and given preliminary data that folliculin deletion may protect against these diseases, my work may provide a novel and promising target for future therapies against these major public health issues.
